Priority is claimed under 35 U.S.C. xc2xa7119 to PCT/GB98/01147, filed Apr. 20, 1998, which corresponds to GB 9707934.7 filed Apr. 18, 1997.
This invention relates to an improved system for the delivery of drugs to mucosal surfaces such as the nose, the eye, the vagina, the rectum and the back of the throat.
Administration of therapeutic agents to mucosa is well known in the art.
A variety of drugs may be administered to the nose, including those intended for the local treatment of nasal diseases, nasal vaccines, and those intended for systemic circulation. Because the nose has a reasonable surface area and a good blood supply, certain lipophilic drugs, such as nicotine and propranolol, can be absorbed rapidly into the blood, resulting in a bioavailability which is similar to that seen with intravenous injection. More polar drugs are less well absorbed, though absorption may be improved by the use of enhancing agents such as surfactants, powders such as microcrystalline cellulose, gelling microspheres (eg. starch), and the bioadhesive polymer, chitosan. Examples of these systems are well known in the art and have been reviewed by Ilium and Fisher in xe2x80x9cInhalation Delivery of Therapeutic Peptides and Proteinsxe2x80x9d, Adjei and Gupta (eds.) Marcel Dekker Inc., New York (1997) 135-184.
In a similar fashion, it is useful to deliver therapeutic agents, such as drugs and vaccines, to the vaginal cavity for a systemic effect or for the local treatment of diseases (particularly infectious diseases such as candidiasis and bacterial vaginitis) as well as for prophylaxis of diseases (e.g. HIV). Locally acting formulations may also be used to deliver contraceptive and spermicidal agents.
Drugs may also be administered to mucosa in the eye and the rectum in order to achieve local effects or for systemic activity.
Considerable advantages in terms of improved efficacy are expected to be gained if a nasally administered formulation were capable of retaining a drug, a vaccine, or DNA intended for local effect, in the nose for relatively long time periods. Previous workers have used a variety of strategies for this purpose.
For example, Illum and others found that biodegradable microspheres based on materials such as starch could delay clearance to a period of hours as compared to a normal half life of clearance of about 10 to 15 minutes (Illum et al, Int. J. Pharm., 39 (1986) 189-199). Surprisingly, such systems were also found to give an improved absorption by affecting the integrity of the tight junctions of the epithelial cells in the nasal cavity and are expected therefore to be best suited to drugs acting systemically.
Similarly, Illum and others have shown that the bioadhesive material chitosan can modify mucociliary clearance with an increase in drug absorption (Illum et al, Pharm Res., 11 (1994) 1186-1189).
It would be most beneficial, due to ease of use and of administration, to have available a simple solution spray system that was suitable for the administration of drugs to the nose and, better still, for the drugs administered via such a system to have a long retention in the nasal cavity. The skilled person may envisage various strategies to this end, including the use of pharmacological agents that decrease mucociliary clearance by a direct effect on the action of cilia, such as cocaine, as well as formulation methods such as environmentally-responsive gels.
Liquids that gel in response to a change in environment are known to those skilled in the art. The environmental change can be temperature, pH or ionic strength or a combination of these factors. Examples-of all of these systems can be found in the prior art literature (see, for example, the smart hydrogel from Gelmed as described by Potts et al in Proceed. Intern. Symp. Control Rel., 24, 335 (1997)). However, the majority of these have been found to be unsuitable for nasal use in man because of factors such as irritation, discomfort (eg. administration of cold solutions), mucosal damage, an unwanted enhancement of drug absorption into the systemic circulation, and many are unavailable due to lack of regulatory approval.
In summary, it would present considerable advantages to provide a single component nasal delivery system, which was in the form of a liquid for ease of administration, and in particular one that gelled in the nose upon contact with the nasal tissues, which could be used to administer, and to modify absorption characteristics, of drugs (therapeutic agents) intended to act locally or systemically. It would also be desirable to provide a system which is well accepted by patients, does not enhance the absorption of drug intended for a local effect into the systemic circulation (as this could lead to side effects), and comprises materials that are approved by regulatory authorities.
Those skilled in the art will appreciate that there are similar problems to be solved in respect of drug delivery for the improved treatment of conditions that affect the vaginal cavity, the rectum, the eye, and the back of the throat, as well as for the improved delivery of vaccines to the local lymphoid tissue, or for the improved delivery of DNA for the transfection of epithelial cells.
For example, drugs intended for the treatment of vaginal infections, or drug free formulations intended to act as vaginal moisturising agents (especially useful in post-menopausal conditions), should spread well in the vaginal cavity and be retained for long periods of time. However, it has been reported that so-called bioadhesive formulations that are intended to be retained in the vaginal cavity for days can be expelled rapidly, with more that 80% of the dose leaving the vagina in less than 2 hours (Brown et al, 14, 1073 (1997)). Thus, it would be advantageous to provide a single component liquid composition that could be inserted into the vagina as a simple liquid and that gelled under the local environmental conditions to give good retention.
For rectal enemas, it would be most beneficial if the liquid enema formed a gel once applied, ensuring close contact with the local environment and preventing early discharge.
Similar problems may be identified in respect of administration to the eye, by virtue of the fact that liquid formulations are rapidly cleared from the eye through drainage down the naso-lacrymal duct. A single component liquid composition that gelled upon application to the eye would be advantageous for the treatment of conditions such as eye infections and inflammation.
Pectins are materials which are found in the primary cell wall of all green land plants. They are heterogeneous materials, with a polysaccharide backbone that is uniform as xcex1-1,4-linked polygalacturonic acid. Various neutral sugars have been identified in pectins such as xylose, galactose, rhamnose, arabinose.
A critical property of pectins, which is known to affect their gelation properties, is the extent to which the galacturonic acid units are esterified. The degree of esterification (DE) of pectins found naturally can vary considerably (from 60 to 90%). The term DE is well understood by those skilled in the art and may be represented as the percentage of the total number of carboxyl groups which are esterified, or as the methoxyl content of the pectin. The respective theoretical maximum for each is 100% and 16% respectively. DE as used herein refers to the total number of carboxyl groups which are esterified. Low DE pectins (ie. those having less than 50% esterification) are usually prepared by the de-esterification of extracted pectins, normally on a bench scale, by way of an enzymatic process, or, on an industrial scale, by the treatment with acid or ammonia in an alcoholic heterogeneous medium. For pectins with a low degree of methoxylation (DM; less than 45%) the gelation properties are known to depend on the DM and the molecular weight of the pectin. The chemistry of low methoxyl pectin gelation is described by Axelos and Thibault in xe2x80x9cThe Chemistry and Technology of Pectinxe2x80x9d, Academic Press, New York, pp. 109-118, (1991).
Various prior art documents discuss the potential use of pectin as a bioadhesive and gelling material. Studies by Smart et al, J. Pharm. Pharmacol. 36, 295 (1984) in relation to the adhesiveness of various materials to mucus have shown that pectin is poorly adhesive in in vitro tests. A tablet capable of adhering to the mucus membrane containing pectin has been described in EP 306 454. Oechslein et al (Int. J. Pharm., 139, 1994), 25-32), have described the potential of various powder formulations to enhance the nasal absorption of the somatostatin analogue peptide octreotide. Pectin (type FPA) powder was used, and gave rise to an increase in the absolute bioavailability of the drug as compared to the drug administered in a saline solution. In none of these documents was the use of a solution formulation containing a pectin with a low DE, or a pectin that gels in contact with nasal secretions, described.
Pectin has also been studied as a mucoadhesive ophthalmic material by Chetoni et al (Bull. Chem. Farm., 135, 147 (1996)). Salt complexes of drugs with pectin for administration to the oral mucosa as patches have been described by Burgalassi et al, World Meet. Pharm. Biopharm. Pharm. Technol., (1995), p. 839, APGI, Paris. Popovici and Szasz (in xe2x80x9cBuccal and Nasal Administration as Altematives to Parenteral Administrationxe2x80x9d, Minutes of a European Symposium (1992), Duchene, D., Ed., Sante, Paris, France. p. 292-6) have described mucoadhesive hydrogels containing cellulose and pectin and a bivalent cation in the form of magnesium. The use of a low DE pectin as a solution that would gel in contact with mucosal surfaces was not described in any of these documents.
U.S. Pat. No. 4,826,683 describes a nasal decongestant containing vegetable oil, aloe vera, zinc, vitamin C, vitamin A, vitamin E, vitamin B6, biotin and fruit pectin. The content of fruit pectin was to a maximum of 2 g per litre. The solubilised fruit pectin supplied by General Foods under the trade name xe2x80x9cCertoxe2x80x9d was preferred. JP 62236862 describes an artificial mucus composed of a mixture of a spinnable water soluble polymer and a polysaccharide, protein or vinyl polymer. Pectin is listed as a suitable polysaccharide, though the type of pectin is not specified.
U.S. Pat. No. 5,147,648 (EP 289 512) describes a pharmaceutical formulation made from at least two components which, when added separately, can form a gel for treating a mucosa. The two components are applied separately to the same area of a mucous membrane. The components may be added simultaneously or sequentially. One of the gel forming solution components includes a calcium salt (eg. calcium gluconate) and the other may include a pectin. There is no suggestion in this prior art document that a solution comprising pectin may be administered as a single component, in the absence of a separately applied solution of calcium ions, which will gel once in contact with the mucosa.
U.S. Pat. No. 5,318,780 describes aqueous pharmaceutical vehicles containing two components, a film forming polymer (eg. pectin) and an ionic polysaccharide, which are then gelled in situ by contacting the mixture with a counter-ion. Polygalacturonic acids such as pectin are mentioned in an extensive listing of representative useful polymers for application in the eye as corneal mastis protective corneal shields. No examples of the use of a pectin solution alone, nor of pectins with a low DE, or pectins that would gel in contact with the mucosa, are disclosed.
The preparation of pectin beads by ionotropic gelation has been described by Aydin and Akburfa (1996) Int. J. Pharm., 137, 133-136.
In summary, although it is known in the art that all pectins will form gels in the presence of calcium ions, for the pectins employed previously in pharmaceutical systems to be applied to mucosal surfaces, it has been hitherto understood that high levels of calcium are needed, which levels are well above physiological concentrations. This has necessitated the utilisation of pectin systems which are applied either in the form of preformed gels, or before or after the addition of exogenous calcium in order to produce a gel in situ. That liquids (especially solutions) comprising low DE pectins may be applied as such, and may gel upon, or just after, application to mucosa is neither described nor suggested in any of the aforementioned prior art documents. Further, the importance of the DE of pectin upon such gelation properties is not mentioned in any of these prior art documents.
We have now found, surprisingly, that certain pectin materials, namely those with a low DE, may be administered in the form of single component, simple liquid formulations (i.e. in an aqueous carrier) which will gel, or can be readily adapted to gel, upon application to mucosa in the nasal, rectal and vaginal cavities, in the eye, or at the back of the throat. We have also found, surprisingly, that gelation may occur at physiologically acceptable pH values in the presence of very much reduced calcium concentrations, ie. those which can be found physiologically in the nasal secretions, as well as in the vaginal lumen, the rectal cavity and the tear fluid of the eye.
According to a first aspect of the invention there is provided a single component liquid pharmaceutical composition for administration to a mucosal surface comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, that gels or can be adapted to gel at the site of application.
We have found, in particular, that such compositions gel, or can be adapted to gel, at the site of, and upon, or just after, application to a mucosal surface in the absence of an extraneously (ie. separately and/or independently) applied (simultaneously or sequentially) solution of calcium (or other divalent metal) ions. There is thus provided a single component liquid pharmaceutical composition for application directly to a mucosal surface comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, which composition is adapted to gel at the site of application in the absence of an extraneous source (eg. solution) of divalent metal ions applied to the same site.
According to a further aspect of the invention, there is provided a kit of parts comprising a liquid pharmaceutical composition for administration to a mucosal surface, comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, provided that the kit does not comprise a solution of divalent metal ions to be added extraneously to said surface.
In particular, there is provided a kit of parts comprising a liquid pharmaceutical composition for administration to a mucosal surface, which composition comprises a therapeutic agent, a pectin with a low DE and an aqueous carrier, and which kit of parts is packaged and presented with instructions to administer said composition to said surface in the absence of an extraneous source of divalent metal ions.
The liquid pharmaceutical compositions for administration to mucosal surfaces comprising therapeutic agent, low DE pectin and aqueous carrier, which are, or are to be, administered as a single component, and which gel, or are adapted to gel, in the absence of an extraneous source of divalent metal ions are referred to hereinafter as xe2x80x9cthe compositions of the inventionxe2x80x9d.
By xe2x80x9cliquidxe2x80x9d composition, we mean a composition which is in the form of a mobile fluid upon application to the mucosa. The compositions of the invention are in the form of an aqueous formulation comprising a solution, a suspension, or an emulsion, including pectin and therapeutic agent, in water. The compositions of the invention will gel, or may be adapted to gel, upon, or shortly (eg. up to 5 minutes) after, application, to a form a solid or semi-solid gel material, which gel is suitable to provide a retaining effect at the site of administration.
By xe2x80x9cdegree of esterification (DE)xe2x80x9d, we mean the percentage of galacturonic acid units which are esterified, for example as described in the article by Walter in xe2x80x9cThe Chemistry and Technology of Pectinxe2x80x9d, Academic Press, New York (1991), p. 192. By xe2x80x9clow DExe2x80x9d, we mean a pectin in which less than 50%, and more preferably less than 35 of the galacturonic acid units are esterified.
By xe2x80x9cextraneous sourcexe2x80x9d of divalent metal ions, we include a separate and/or independent (ie. exogenous) source of such ions. Ions which are present in a gel resulting from administration of a composition of the invention to a mucosa are not derived from either the composition, or from the bodily secretions of the patient to which the composition is to be applied (eg. endogenous ions derived from nasal secretions, tear fluid, etc.). Divalent metal ions which may be mentioned include calcium ions.
According to a further aspect of the invention, there is provided a pharmaceutical gel composition obtainable by applying a liquid composition, comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, to a mucosal surface of a mammalian patient in the absence of extraneous application of a solution of divalent metal ions to said surface.
The gels so formed upon contact with mucosal surfaces will contain only endogenous divalent metal ions (i.e. those derived directly from bodily secretions) and will not include exogenous divalent metal ions (i.e those derived from an extraneous source). According to a further aspect of the invention there is provided a pharmaceutical gel composition, which gel comprises a therapeutic agent and a pectin with a low DE, which gel is obtainable by applying a liquid composition, comprising said therapeutic agent and pectin in an aqueous carrier, to a mucosal surface, and which gel is substantially free of divalent metal ions derived from an extraneous source applied to said mucosal surface before, or at the same time as, or after, said liquid composition is applied.
Because the compositions of the invention are not added in conjunction with an extraneous source of such ions, by xe2x80x9csubstantially freexe2x80x9d of divalent metal ions, we mean greater than 97%, preferably greater than 99%, more preferably greater than 99.9%, and especially greater than 99.99% free.
Pectins with a low DE can be obtained from known sources, or can be obtained via de-esterification of high DE pectins (which may be obtained from, for example, Sigma Fine Chemicals), in accordance with known techniques, such as those described in the article by Rollin in xe2x80x9cIndustrial Gumsxe2x80x9d, Academic Press, New York (1993) p. 257, or as described hereinbefore. Low DE pectin may, for example, be obtained from Copenhagen Pectin A/S as the commercial material known as Slendid Type 100 and Slendid Type 110. These pectins have been extracted from citrus peel and standardised by the addition of sucrose. The standardisation process is as described by Rollin in the abovementioned article. The DE is less than 50% for both pectins and of the order of 10% for type 100 and 35% for type 110. Further materials which may be employed include GENU pectin types LM 1912 CS and Pomosin pectin types LM 12 CG and LM 18 CG.
The compositions of the invention may be prepared by dissolving or dispersing the pectin of low DE and therapeutic agent in an aqueous system, to form a solution, a suspension or an emulsion in accordance with known techniques. For example, the therapeutic agent may be dissolved in a prior prepared aqueous solution of the pectin, or may be added as, or to form, a suspension in an aqueous system, where the drug particles are less than 100 microns in size, preferably between 1 and 20 microns. Alternatively, drug may be dissolved or suspended in a suitable is oily vehicle such as a vegetable oil, and then dispersed into the aqueous pectin solution to form an emulsion. It will be appreciated by those skilled in the art that the type of aqueous formulation so developed will depend upon to mucosa to be treated, as well as the dose, and the physical characteristics and properties, of the drug (e.g. its solubility, basicity etc.).
The concentration of low DE pectin in compositions of the invention depends upon the nature of the pectin, the presence of other components, and other factors which influence gelation properties of the composition (see below), but may be from 1 g/L to 100 g/L, and is preferably from 1 g/L to 50 g/L, more preferably from 2 g/L to 10 g/L and especially from 5 g/L to 10 g/L.
Compositions of the invention may be used with a view to the prevention of a major problem in the delivery of drugs to the nose for local treatment, namely the rapid mucociliary clearance mechanism. This natural process, which removes deposited material from the front of the nose to the throat, can clear material from the nose with a half-time of about 10 to 20 minutes. Such clearance rates can be measured readily in man using the saccharin clearance test or by gamma scintigraphy (Aspden el al, J. Pharm. Sci., 86, 509 (1997); Illum et al, Int. J. Pharm., 39 (1987) 189-199).
Compositions of the invention may be employed to retain a therapeutic agent which is intended to act locally at a mucosal surface for a relatively long period when compared to mucosal delivery systems known in the art. If the therapeutic agent is easily absorbed, absorption may be retarded, thus keeping more of the drug at the site of application, where it is needed.
Therapeutic agents which may be employed in the compositions of the invention include, for nasal administration, drugs that are employed locally to treat conditions such as rhinitis, viral infections, as well as those which act as decongestants. The compositions of the invention may also be used as a way of improving the delivery of vaccines to the nose associated lymphoid tissue and for the better presentation of DNA for the transfection of nasal epithelial cells.
The following list of therapeutic agents are suitable for use in the compositions of the invention, for local treatment of a mucosal surface, is provided by way of illustration and is not meant to be exclusive: antiviral agents such as ICAM-1, pirovadir, acylovir, bromovinyldeoxyuridine, xcex1, xcex2 and xcex3-interferon, zidovudine; decongestants such as oxymetazaline, antiallergic agents, such as sodium cromoglycate and budesonide; steroids, such as fluticazone; vaccines, such as DNA, influenza, pertussis, measles and diphtheria vaccines; antibacterial agents, antifungal agents, such as ampliotericin, nystatin; contraceptive and/or spennicidal agents; antibodies especially for the treatment of RSV infection in children; prophylactic agents against HIV; antihistamines, such as diphenhydramine hydrochloride; genes.
Combinations of the abovementioned therapeutic agents may also be employed.
Compositions of the invention may also be employed to control the plasma level versus time profile for readily absorbable drugs which are intended to act systemically (ie. to give a flatter profile), either by altering the rate of transport into the general circulation, or by retarding absorption of readily absorbable drugs. This can, for example, be of importance when side effects from high peak plasma levels are to be avoided.
The compositions of the invention may thus be used for the modification of the systemic absorption of mucosally administered drugs, including, but not limited to, apomorphine, nicotine, hyoscine hydrobromide, lignocaine, fentanyl, naratriptan, pheromones and propranolol.
Combinations of the abovementioned therapeutic agents may also be employed.
For the avoidance of doubt, the term xe2x80x9ctherapeutic agentsxe2x80x9d is intended herein to include agents which are suitable for use in the treatment, and in the prevention, of disease.
The compositions of the invention may be used to treat/prevent diseases/conditions in mammalian patients depending upon the therapeutic agent(s) which is/are employed. For the above, non-exhaustive lists of locally acting and systemic drugs, diseases/conditions which may be mentioned include those against which the therapeutic agent(s) in question are known to be effective, and include those specifically listed for the drugs in question in Martindale, xe2x80x9cThe Extra Pharniacopoeiaxe2x80x9d, 31st Edition, Royal Pharmaceutical Society (1996).
Preferred drugs include nicotine and apomorphine.
The amount of therapeutic agent which may be employed in the compositions of the invention will depend upon the agent which is used, and the disease to be treated, but may be in the range 0.01 to 40% w/w. However, it will be clear to the skilled person that suitable doses of therapeutic agents can be readily determined non-inventively. For example, estimates of dosage can be made from known injectable products assuming that from 0.1 to 90% of the dose is absorbed. Suitable single unit doses are in the range 10 xcexcg to 500 mg depending upon the therapeutic agent(s) which is/are employed and the route of administration. Suitable daily doses are in the range 10 xcexcg to 1 g/day depending upon the therapeutic agent(s) which is/are employed and the route of administration.
Most compositions comprising drug and a low DE pectin will gel upon application at the site of application, i.e. upon, or shortly (e.g. up to 5 minutes) after, contact with the relevant mucosal surface. However, in some formulations, the nature of the drug and/or the pectin which is/are employed may require that the composition is adapted such that it gels upon, or shortly (e.g. up to 1 minute) after, contact. This may be achieved readily via techniques which are well known to those skilled in the art:
For example, the concentration of pectin may be selected such that the aqueous formulation will gel once in contact with the mucosal surface.
Furthermore, the addition of monovalent ions to aid the gelling process may be required (for example, simple monovalent electrolytes, eg. NaCl, may be added to adapt the liquid formulation to gel, as well as to provide isotonicity).
The quantity and nature of the drug in the aqueous formulation may also have an influence on the gelation properties. For example, the addition of a high level of a certain drugs, including those which are weak bases (such as nicotine), which are known to form reversible complexes with anionic materials such as pectin, may require a change in the ratio between drug and pectin, so that preferably 30%, more preferably 50%, and most preferably 60%, of the negative charges on the pectin molecule are uncomplexed.
Alternatively, sugars in the form of, for example, sucrose can be added to the formulation to aid gelation. Non-ionic polysaccharides (such as hydroxypropyl methyl cellulose) may also be used.
The pH of the composition has also been found to affect gelation properties. The pH of the compositions of the invention may be from 2 to 9, more preferably from 3 to 8 and most preferably from 4 to 7, taking into account the gelation properties of the composition and the properties of the therapeutic agent. For example, in general, we have found that the lower the DE of the pectin, the lower the pH at which the composition will gel. pH may be adjusted in accordance with techniques which will be well known to those skilled in the art, such as the addition of pharmaceutically acceptable buffering agents, especially those of low ionic strength. Axelos and Thibault in xe2x80x9cThe Chemistry and Technology of Pectinxe2x80x9d, Academic Press, New York, pp. 109-118, (1991) describe how the gelation properties of low DE pectin solutions are somewhat sensitive to pH and ionic strength.
The abovementioned techniques, which may be used to adapt the compositions of the invention to gel, may be investigated and determined in the normal course of routine experimentation by those skilled in the art. Combinations of these techniques may also be employed in order to affect gelation properties.
The compositions may also contain other additives in the form of pharmaceutical excipients, such as preservatives (e.g. low concentrations of materials such as sodium metabisulphate), stabilisers, flavouring agents, absorption enhancers such as bile salts, phospholipids, as well as agents which are known to interact with the drug, for example to form inclusion or salt-bridge complexes, and promote a controlled release in the nasal cavity from the formed gel, such as cyclodextrins and ion exchange resins. Additional pharmaceutically acceptable excipients which may be added to the compositions of the invention include agents such as glycerol.
According to a further aspect of the invention there is provided a process for the preparation of a composition of the invention which comprises mixing together the therapeutic agent and the pectin in the aqueous carrier.
The compositions of the invention may be administered in suitable dosage forms, in accordance with techniques, and via delivery devices, all of which are known to those skilled in the art. For example, for nasal delivery, the compositions of the invention are preferably administered by way of a spray device, for example the Pfeiffer metered dose pump or the Valois metered dose pump, or via a liquid free flow system (such as nasal drops). For vaginal and rectal administration (infusion) a syringe-type applicator may be used, or plastics ampoules fitted with a suitable nozzle, where the contents of the ampoule can be delivered to the vaginal or rectal surface via the application of a slight pressure. Suitable systems for delivery of the compositions of the invention to the back of the throat include spray devices which are well known to those skilled in the art. Suitable systems for delivery of the compositions of the invention to eye include liquid free flow system which are well known to those skilled in the art (such as eye drops).
The compositions of the invention have the advantage that they may be readily administered to mucosal surfaces in the form of single component, simple liquid formulations, in the absence of an additional component comprising an extraneous source of divalent metal ions, using devices which are well known to those skilled in the art. The compositions of the invention also have the advantage that they gel upon, or shortly after, contact with mucosa, at physiologically acceptable pHs, in the presence of endogenous calcium (only) found physiologically in the nasal secretions, as well as in the vaginal lumen, the rectal cavity and the tear fluid of the eye.
Compositions of the invention also have the advantage that they may be used to retain a locally-acting drug at a mucosal surface, or to control drug absorption into the systemic circulation.
Compositions of the invention may also have the advantage that they may be well accepted by patients, and may comprise materials that are approved by regulatory authorities.
According to a further aspect of the invention there is provided a method of treatment of a patient which comprises the administration of a liquid pharmaceutical composition, comprising a therapeutic agent, a pectin with a low DE and an aqueous carrier, which composition gels or is adapted to gel at the site of application, to a mucosal surface of said patient in the absence of extraneous application of a solution of divalent metal ions to said surface.
There is provided further a method of treatment or prophylaxis of a disease which comprises administration of a composition of the invention including a therapeutic agent which is effective against said disease to a mucosal surface of a patient in need of such treatment in the absence of extraneous application of a solution of divalent metal ions to said surface.